Capsaicin, the compound that gives chili peppers their heat, activates the TRPV1 pain receptor, which also responds to high temperatures, inflammation and tissue damage. However, a new study has found that this receptor may function differently depending on the stimulus that activates it. The discovery could help scientists develop more targeted painkillers with fewer side effects.
The study, conducted by researchers at the University of California, Davis, School of Medicine, was published in the journal Proceedings of the National Academy of Sciences (PNAS).
TRPV1 is found on nerve cells that detect pain. It plays an important role in transmitting pain signals and has long been considered a potential target for developing painkillers that do not cause the dependence associated with opioid drugs. However, attempts to block its activity have encountered a major obstacle: TRPV1 also helps regulate body temperature, and interfering with it can disrupt this process.
Previously, scientists believed that the receptor adopted roughly the same open state regardless of which stimulus triggered its activation. The new findings challenge this assumption.
"Our results show that the receptor is more complex than previously thought. Different stimuli appear to stabilize different open states, each with its own functional properties," explained the study's first author, Bo Hyun Lee, who previously worked in Zheng's laboratory at the University of California, Davis.
During the experiments, the researchers examined how TRPV1 responded to capsaicin, resiniferatoxin — an extremely potent irritant derived from a plant in the spurge family — protons, which create an acidic environment during tissue damage and inflammation, the chemical compound 2-APB, and heat.
Measurements of electrical currents flowing through individual channels showed that different stimuli produced different levels of conductivity. Additional experiments, including measurements of charged particle movement, fluorescence-based observations of changes in the protein, and computer modeling, pointed to differences in the channel's configuration.
"We obtained consistent results using several independent experimental methods. They showed that the channel pore appears different when activated by different stimuli," said the study's senior author, Professor Jie Zheng.
The researchers also discovered an unexpected effect: when two stimuli acted on the receptor simultaneously, the channel opened more slowly rather than more quickly. This suggests that different activation mechanisms can interfere with one another.
The scientists believe that understanding the different states of TRPV1 could eventually make it possible to develop drugs that primarily target pain-related mechanisms without disrupting the body's ability to sense heat and regulate temperature. For now, however, this remains a potential avenue for drug development, and further research will be needed to create new treatments.
Follow NEWS.am Medicine on Facebook and Twitter